Device for delivering drug to biological environment

ABSTRACT

A self-powered device for delivering drug is disclosed. The device comprises (1) a substantially rigid housing, (2) a collapsible container storing a drug and having a passageway for delivering the drug in the housing, and (3) an expandable laminate positioned between the housing and the container. The laminate comprises (a) a lamina formed of an absorbent material laminated to (b) a lamina placed adjacent to the container and formed of a swellable hydrophilic polymer. In operation, when the device is in a biological environment, fluid from the environment is imbibed by the laminate into the housing causing the laminate to expand and exert pressure on the container, thereby collapsing the container and concomitantly pumping drug through the passageway from the device at a correspondingly controlled rate over a prolonged period of time.

FIELD OF THE INVENTION

This invention pertains to a self-powered, integrated device fordelivering drug. More particularly, the invention relates to a devicethat is simple in construction and delivers drug in response to forceapplied by a swellable hydrophilic polymer on a container storing drug.The force causes the container to continuously collapse and decrease itsinternal volume, thereby propelling drug from the device.

BACKGROUND OF THE INVENTION

In recent times, much effort has been devoted to developing new anduseful devices for delivering drugs to a drug receptor site. Generally,these devices deliver a drug by diffusion from a non-erodible polymermatrix, by release from an erodible polymer matrix, or by delivery froman osmotic device. While, these devices are useful, serious shortcomingsare associated with their use. For example, devices which contain drugdispersed or dissolved in a non-erodible matrix often do not exhibitzero order drug release kinetics since the drug is first removed onlyfrom the surface layers of the matrix and the distance drug must diffuseto the surface from within the matrix increases with time. For this kindof a device, essentially t^(-1/2) kinetics are observed. A seriousshortcoming for devices made from an erodible polymer is the polymer'sinability to dissolve or erode at a uniform rate over time.Correspondingly, for these devices, drug is not delivered to thereceptor at a uniform rate over time. One shortcoming observed forosmotic devices is the need for the drug to be soluble in fluid imbibedinto the device, since a drug that cannot act as its own osmoticallyeffective solute will not imbibe fluid, and without imbibition, drug isnot pumped from the device. In view of the above presentation, it willbe appreciated by those versed in the art that a critical need existsfor a drug delivery device that is simple in construction, easy to make,and can deliver drug at a controlled rate over time to a drug receptorsite.

OBJECTS OF THE INVENTION

Accordingly, it is an immediate object of this invention to makeavailable a new and useful drug delivery device that overcomes theshortcomings known to the prior art.

Another object of the invention is to provide a drug delivery devicethat is simple in construction and which device exhibits all of thepractical benefits of controlled and continuous administration ofvarious drugs to animals and humans over a prolonged period of time.

Yet another object of the invention resides in the provision of animproved device which enables high concentrations of active drug to beadministered therefrom, and which concentrations of drug will notexhibit the tendency to be leached from the device, nor be decreased inpotency when the device is administering drug to a receptor.

Still another object of the invention is to provide a drug deliverydevice that is easy to manufacture and will release drug in solution,gel or semi-solid formation, at a controlled rate over a prolongedperiod of time.

Other objects, features and advantages of this invention will becomemore apparent from the following description when taken in conjunctionwith the accompanying specification, drawings and the claims.

SUMMARY OF THE INVENTION

The invention concerns a device for delivering drug to a biologicalenvironment of use. The device comprises an expandable laminatesurrounding a collapsible container filled with drug and positioned in arigid housing member. In operation, the device releases drug in responseto the laminate imbibing fluid and expanding, thereby exerting pressureon the container, which then collapses and urges drug from the device.

BRIEF DESCRIPTION OF THE DRAWINGS

In the drawings, which are not drawn to scale, but are set forth toillustrate various embodiments of the invention, the figures are asfollows:

FIG. 1 is a front view of a dispensing device made according to theinvention;

FIG. 2 is a cross-sectional view of the device of FIG. 1 through 2--2thereof illustrating the structure of the device; and,

FIG. 3 is an illustration of the device of FIGS. 1 and 2 depicting thedevice in operation and dispensing drug therefrom.

In the drawings and specification, like parts in related Figures areidentified by like numbers. The terms appearing earlier in thespecification and in the description of the drawings as well asembodiments thereof, are further described elsewhere in the disclosure.

DETAILED DESCRIPTION OF THE DRAWINGS

Turning now to the drawings in detail, which are an example of a new anduseful device for dispensing a drug, and which example is not to beconstrued as limiting, one device is indicated in FIG. 1 by numeral 10.In FIG. 1, device 10 consists essentially of a housing 11 shaped, sizedand adapted for placement in an environment of use. Housing 11 is madeof a substantially rigid wall forming material, which wall surrounds anddefines an internal space for receiving a container 12. Housing 11 hasat least one opening 11a or it can have more than one opening throughwhich container 12 communicates with the exterior of device 10. Adetailed discussion of this and other materials used for manufacturingdevice 10, including drugs that can be dispensed by device 10, ispresented later in this application. Device 10 comprises a container 12placed within housing 11 for storing drug, which container 12 is seen indashed lines in FIG. 1 and it is formed of a material that collapses inresponse to pressure applied against the exterior surface 13 ofcontainer 12.

Referring to FIG. 2, dispensing device 10 of FIG. 1 is seen incross-section along line 2--2 of FIG. 1. As seen in FIG. 2, device 10comprises a housing 11 or body member formed of a substantiallyshape-retaining rigid material having positioned within container 12.Container 12 is surrounded by a laminate 14 comprising lamina 15 andlamina 16. Lamina 15 is positioned adjacent to the interior surface ofhousing 11 distant from container 12, and it, 15, is formed of anabsorbent porous or fibrous material capable of imbibing external fluidinto housing 11. Fluid can enter device 10 through opening 11a or inanother embodiment it can enter through one or a multiplicity ofpassageways or holes in housing 11. Lamina 16 is in laminar arrangementwith lamina 15, and lamina 16 is positioned adjacent to the exteriorsurface 13 of container 12, distant from housing 11. Lamina 16 is formedof a swellable hydrophilic polymeric material that can imbibe fluidpresent in housing 11 for increasing its space-occupying dimensions.Container 12 is formed of an elastomeric (or other low-modulus) materialand it, 12, has a passageway 17 for dispensing drug 18 from device 10 toa biological environment of use. Passageway 17, in one embodiment, isformed by the wall of container 12 terminating in passageway 17 which isprojected through opening 11a in housing 11. In another embodiment, notshown, passageway 17 is an aperture in the wall of container 12 and itconnects to a conduit or tube extended through opening 11a for releasingdrug 16 from device 10.

In FIG. 3, device 10 is seen dispensing drug 18 through passageway 17from container 12. In operation, device 10 functions by laminate 14comprised of lamina 15 and lamina 16 slowly imbibing water or biologicalfluid into laminate 14, causing lamina 16 to swell and expand fromposition 19 to 19a, thereby exerting pressure against container 12. Thepressure applied against the entire exterior surface 13 of container 12causes surface 13 to slowly collapse to position 13a. The collapse ofsurface 13 correspondingly decreases the internal volume of container 12thereby expelling drug 13 at a predetermined and controlled rate throughpassageway 17 to the environment of use over a prolonged period of time.The size of passageway 17 can in an optional embodiment be givenpredetermined dimensions as an additional aid for controlling the rateof drug release by device 10.

While FIGS. 1 through 3 are illustrative of various devices that can bemade according to the invention, and it is to be understood thesedevices are not to be construed as limiting, as they can take a widevariety of shapes, sizes and forms for delivering drug to varied andmany different environments of use. For example, device 10 can bemanufactured for dispensing drug 18 to animals, including warm-bloodedmammals, humans, household, farm, sport and zoo animals. Device 10 canbe made for dispensing drug 18 to body cavities and body openings suchas for oral administration, for use as intramusclar implants,intrauterine, vaginal, cervical, rectal, nasal, ear, and dermal devices.Device 10 also can be made for use as an artifical gland and forarterial and venous administration of drug 18. The device can be madefor use in homes, hospitals, nursing homes and clinics.

DETAILED DESCRIPTION OF THE INVENTION

Device 10, as used for the purpose of this invention consists of ahousing 11 made of a substantially rigid polymer material. This materialpermits pressure to be exerted against it without any major change inits shape or dimensions, thereby assuring that pressure generated indevice 10 is exerted against container 12. Housing 11 can optionally beformed of a member selected from the group consisting of an impermeablematerial with at least one opening, a permeable material, a microporousmaterial, and the like. Representative polymers suitable for forminghousing 11 include polyethylene, polypropylene, polytetrafluoroethylene,polyamides, polyformaldehyde, polystyrene, polycarbonate, polyacrylate,polymethacrylate, polyacrylonitrile, polyvinylchloride, and the like.Generally, the thickness of housing 11 will vary depending on the deviceand its use, and it will usually have a thickness of 1 mm to 50 mm ormore.

Representative of absorbent materials suitable for forming lamina 15 areporous materials derived from animal and plant origins includig wool,cotton, straw, flax and other vegetable fibers. Exemplary materialsinclude cotton mats or pads of fibers, artificial regenerated cellulosesponge, blotting paper, tea bag paper, and matted, felted, porous orfibrous sheets, or other means such as absorbent bleached and unbleachedpaper. The thickness of lamina 15 will vary depending on the device, andit will usually have a range of 0.50 mm to 50 mm, or more.

Representative of swellable hydrophilic polymers suitable for forminglamina 16 are, for example, lightly cross-linked predominantly linearpolymers covalently or ionically cross-linked, (such cross-links beingformed by covalent or ionic bonds), which interact with biological andother aqueous solutions by swelling or expanding to some equilibriumstate. These polymers swell or expand to a very high degree withoutdissolution, usually exhibiting a 5 to 50 fold volume increase.Materials for this purpose include poly(hydroxyalkyl methacrylates),poly(N-vinyl-2-pyrrolidone), anionic and cationic hydrogels,polyelectrolyte complexes, poly(vinyl alcohol) having a low acetateresidual and cross-linked with glyoxal, formaldehyde, or glutaraldehyde,methylcellulose cross-linked with a dialdehyde, a mixture of agar andsodium carboxymethyl cellulose, a water-insoluble, water-swellablecopolymer produced by forming a dispersion of finely divided copolymerof maleic anhydride with styrene, ethylene, propylene, butylene orisobutylene cross-linked with from about 0.001 to about 0.5 mole of apolyunsaturated cross-linking agent per mole of maleic anhydride in thecopolymer as disclosed in U.S. Pat. No. 3,989,586, water-swellablepolymers of N-vinyl lactams as disclosed in U.S. Pat. No. 3,992,562, andthe like. Generally, the lamina 16 will have a thickness of about 5 mmto 50 mm, or higher, and in a presently preferred embodiment it willhave an expanded or swelled thickness state approximately equal to theinternal diameter of container 12 to produce a complete collapse ofcontainer 12 and discharge of drug 18 therefrom.

Representative materials suitable for manufacturing container 12 arematerials that can be designed into a shaped container, elastomeric tubeor capsule, which collapses in response to externally applied pressure,thereby dispensing drug. Typical elastomeric polymers include naturalrubber often identified by the synonyms poly(2-methyl-1,3-butadiene) andcis-1,4-polyisoprene, gutta percha or trans-polyisoprene, cyclisedrubber, synthetic isoprene rubber, butadiene rubber, styrene-butadienerubbers, nitrile rubber, chloroprene rubbers, ethylene-propylenerubbers, butyl rubbers, and the like as disclosed in Handbook of CommonPolymers, by Scott and Roff, Sections 29 through 40, 1971, published bythe Chemical Rubber Company, Cleveland, Ohio. Container 12, formed ofthe above representative materials, can have its wall of varyingthickness, usually about 2 mm to 50 mm, or more depending on thecontainer and its use. Container 12 can be manufactured with one or morepassageways for dispensing drug, or it can be made to form a passagewaywhen the device is in the environment of use. In this embodiment, oneend of container 12 is closed with a water-soluble plug of an erodiblematerial, such as polyvinyl alcohol, gelatin, or the like that erodes inthe environment of use to form a small-diameter orifice. In anotherembodiment, a preformed orifice having a cross-section of 1 to 10 milscan be temporarily closed with a plug, which plug is ejected when thecontainer collapses in use, thereby forming the orifice in situ.

Exemplary drugs that can be administered according to the spirit of theinvention include locally and systemically acting drugs. These drugsinclude a member selected from the group consisting of physiologicallyand pharmacologically acting drugs such as gastrointestinaladministrable drugs, central nervous system acting drugs, hypnotic,sedative, psychic energizer, tranquilizer, anticonvulsant,antiparkinson, muscle relaxant, analgesic, antipyretic,anti-inflammatory, anesthetic, antispasmodic, antimicrobial, antiviral,antiulcer, hormonal, sympathomimetic, diuretic, hypoglycemic, vitamins,anticontraceptive, and ophthalmic drugs. These beneficial drugs andtheir dose amount for humans are known to the art in Drill'sPharmacology in Medicine, edited by DiPalma, Joseph R., 1965, publishedby McGraw-Hill Book Company, New York, in Pharmacological Basis ofTherapeutics, by Goodman and Gilman, 4th Edition, 1970, published by theMaMillian Co., London and in U.S. Pat. No. 3,977,404, which patent isassigned to the ALZA Corporation of Palo Alto, Calif., the assignee ofthis patent application. The drug in the container can be mixed with apharmaceutically acceptable liquid carrier such as water, saline,cottonseed oil, sesame oil, ethyl oleate, isopropyl myristate, propyleneglycol and the like. The drug can be present in solution, in semi-solidor paste formulation, in a thixotropic state and the like, which permitscontrolled dispensing of drug from the device. Pharmaceuticallyacceptable carriers and the like are known to the art in Remington'sPharmaceutical Sciences, 14th Edition, pages 1461 to 1762, 1970,published by the Mack Publishing Company, Easton, Pa.

Representative examples of drugs that can be dispensed from an oraldevice comprising (1) a rigid polyethylene housing manufactured with anopening and having placed therein (2) a container shaped and sized likea 000 capsule with a single orifice for releasing drug and formed ofnatural rubber, which container is surrounded by (3) a monolithiclaminate of polyvinyl alcohol cross-linked with glyoxal directly coatedupon teabag paper without filling the pores of the paper, and a drugformulation in the container such as (4) tetracycline hydrochloride inpolyethylene glycol 200, or (5) a formulation consisting of a suspensionof 0.1 mg of digitoxin in a carrier medium of water, 17 weight percent,which formulation in either embodiment are dispensed at a controlledrate from the device, when the device is in the environment of use. Inanother embodiment, the housing is made with a multiplicity of holes foradmitting fluid into the housing during the operation of the device.

Although the foregoing invention has been described in detail by way ofillustration of a preferred embodiment and examples for purpose ofclarity of understanding, it will be understood that certain changes andmodifications may be practiced within the scope and spirit of theinvention.

We claim:
 1. A drug delivery device comprising:(a) a drug; (b) a housinghaving a shape-retaining wall defining an internal space, said housinghaving at least one opening connecting the space with the exterior ofthe device; (c) a container in the housing, said container having acollapsible wall surrounding a reservoir for storing the drug and apassageway for delivering drug from the container to the exterior of thedevice; and, (d) a laminate in the housing surrounding the containercomprising a lamina of an absorbent material and a lamina of a swellablehydrophilic cross-linked polymer, said laminate capable of imbibingfluid into the housing thereby causing the laminate to expand and exertpressure on the container which collapses said container andconcomitantly pumps drug through the passageway from the device at acontrolled rate over a prolonged period of time.
 2. The drug deliverydevice according to claim 1, wherein the lamina formed of an absorbentmaterial has a surface in contact with the housing and a surface inlaminar arrangement with the lamina formed of the swellable hydrophilicpolymer.
 3. The drug delivery device according to claim 1, wherein thelamina formed of the swellable hydrophilic polymer has a surface incontact with the container.
 4. The drug delivery device according toclaim 1, wherein the lamina formed of the absorbent material is formedof a member selected from the group consisting of wool, cotton, straw,flax, paper and mixtures thereof.
 5. The drug delivery device accordingto claim 1, wherein the container is formed of a member selected fromthe group consisting of natural rubber, gutta percha, cyclised rubber,synthetic isoprene rubber, butadiene rubber, styrene-butadiene rubber,nitrile rubber, chloroprene rubber and ethylene-propylene rubber.
 6. Thedrug delivery device according to claim 1, wherein the swellablehydrophilic polymer is cross-linked and it is a member selected from thegroup consisting of cross-linked poly(hydroxyalkyl methacrylates),poly(N-vinyl-2-pyrrolidone), polyelectrolyte complexes, poly(vinylalcohol) cross-linked with glyoxal, formaldehyde or glutaraldehyde, andcross-linked celluloses.
 7. The drug delivery device according to claim1, wherein the drug is a member selected from the group consisting oflocally and systemically acting gastrointestinal, central nervoussystem, hypnotic, sedative, psychic energizer, tranquilizer,anticonvulsant, antiparkinson, muscle relaxant, analgesic, antipyretic,anti-inflammatory, anesthetic, antispasmodic, antimicrobial, antiviral,antiulcer, hormonal, sympathomimetic, diuretic, hypoglycemic, andanticontraceptive drug.
 8. The drug delivery device according to claim1, wherein the drug in the container is mixed with a pharmaceuticallyacceptable carrier.